Nitric oxide synthase plays an essential role in the proper functioning of vital processes in respiratory, cardiovascular, nervous, and immune systems, and recent advances have shown that improper enzyme function has been linked to the onset of cancer, stroke, and neurodegenerative diseases. Isoform-selective nitric oxide synthase inhibitors have been shown to modulate the activity of these enzymes and help treat numerous human diseases. Alsmaphorazine A, a monoterpene indole alkaloid isolated in small quantities from Alstonia pneumatophora, has shown promising inducible nitric oxide synthase inhibition in lipase stimulated LPS-stimulated J774.1 macrophage cells (IC50=49.2 M) in a dose-dependent manner without affecting cell viability. No members of the alsmaphorazine family have been prepared by total synthesis since their discovery, so synthetic access to these compounds and unnatural analogs would enable their evaluation as nitric oxide synthase inhibitors or potential therapeutics for other diseases. This proposal describes a concise approach to the total synthesis of the unique hexacyclic core of alsmaphorazine A from simple starting materials and outlines the extension of the synthetic route to alsmaphorazine B and numerous synthetic derivatives. The approach employs an intramolecular Diels-Alder, intra- or intermolecular Heck, and (1,3)-dipolar cycloaddition to secure the caged heterocyclic framework which bears 1,2-oxazinane, isoxazolidine, and indoleneine moieties. This flexible synthetic route enables rapid evaluation of key transformations and facile modification for asymmetric synthesis or preparation of unnatural alkaloid analogs.